Comparison of Risk Factors Related to Intraventricular Hemorrhage between Preterm Infants Born After Normal and in Vitro Fertilization Conceptions.

Objectives
We aimed to compare the level of significance of risk factors related Intraventricular hemorrhage (IVH) between preterm infants born after IVF and non-IVF conceptions.


Materials & Methods
This historical cohort study was done in four Iranian Hospitals in 2013-2014. Overall, 155 preterm newborns were divided into case (IVF) and control (normal conception) groups. Both groups' demographic data were extracted and recorded. The incidence of IVH and its grades were compared between case and control groups. Significant related risk factors were also considered.


Results
No differences were observed between 2 groups except for gestational age and mode of delivery. The incidence of IVH especially grades II and III were significantly higher in the case group (P=0.003). Results showed no correlations between Gestational age (GA), birth weight and number of gestations with the incidence of IVH in the case group (0.059, 0.85 and 0.49, respectively). On the other hand, among GA, birth weight and number of gestations; multi gestations (P=0.0001) was an effective risk factor for IVH occurrence in the controls.


Conclusion
The incidence of IVH in the IVF group was significantly higher than in the non-IVF group. IVF as an independent risk factor may cause high-grade IVH; however, in the controls, multi gestational pregnancy (P=0.0001) was an effective risk factor for IVH occurrence.


Introduction
Intraventricular hemorrhage (IVH) as an important cause of neonatal morbidity and mortality is frequently documented among premature infants (1). There are inverse correlations between the risk of IVH and neonate's gestational age or birth weight (2). The incidence of symptomatic IVH is 0.27-0.49 per 1000 live births (1). This rate among extremely low birth weight neonates was reported higher than 27% (3). Depending on types of IVH (epidural, subdural, subarachnoid, intraventricular and intraparenchymal) neurological sequels and developmental disorders are common (4,5). Although both low birth weight and gestational age are the major risk factors, other maternal and neonatal conditions are involved; smoking, breech presentation, gender, premature rupture of membranes, intrauterine and post-natal infections, mode of delivery, prolonged labor, hypercapnia or rapid bicarbonate infusion, cerebral blood flow disturbance, hypotension, metabolic, hematologic and respiratory complications (2,(6)(7)(8).
Ten percent of couples suffer from infertility and are introduced for in vitro fertilization (IVF) as an effective treatment (9) Overall, 517 preterm babies born after IVF and natural conception, preterm mortality and morbidity did not differ between the 2 groups, except for IVH (2,(10)(11)(12).
Iran as one of the pioneers of ART (assisted reproductive techniques) in Middle East from 1980, now has more than hundreds of IVF cycles a year (13). Many studies have investigated the effects of IVF pregnancies on neonatal mortality and morbidity recently (14)(15)(16). Some studies also have determined risk factors for Intraventricular Hemorrhage in Infants born after ART (10)(11)(12). We aimed to compare the level of significance of risk factors related IVH between preterm infants born after IVF and non-IVF conceptions.

Material &Methods
In this historical cohort study, newborns with gestational age<34 wk born and hospitalized at We excluded newborns due to lack of data, receiving prophylactic medication like indomethacin, death before hospital discharge, chorioamnionitis cases and urgent cesarean sections. The incidence of IVH and its grades were compared between case and control groups. Significant related risk factors were also considered.

Results
There were 93 and 62 preterm newborns in the control and case groups, respectively. With regard to demographic characteristics, no differences were observed between 2 groups except for gestational age and mode of delivery; mean gestational age in the control group was significantly lower than in the case group (30.19 vs. 31.48 wk, P=0.001) ( Table 1). The mode of all deliveries in the case group and in 84% of the control group was C/S section (P=0.001).
The incidence of IVH especially grades II and III were significantly higher in the case group (P=0.003). Grade IV IVH was not seen in either group. The number of twin and triplet pregnancies were significantly higher in the case group than in another group (P=0.0001). Comparison of variables between 2 groups is demonstrated in Table 2. Regarding to find correlations between the incidence of IVH and some risk factors like GA, birth weight and number of gestations, statistical analysis was also performed within each group.
Results showed no correlations between GA, birth weight and number of gestations with the incidence of IVH in the case group (P=0.059, P=0.85, and P=0.49, respectively). On the other hand, among above variables, multi gestational pregnancy was an effective risk factor (P=0.0001) for IVH occurrence in the controls (  pregnancy as a significant risk factor for IVH (11).
The incidence of IVH among preterm neonates in the IVF group was significantly higher than those in the non-IVF group (P<0.001) (12). On the other hand, a cohort study showed no significant difference with regard to the IVH incidence among 90 very premature infants in 2 groups; born after IVF or normal conception (17).
Mean gestational age in the control group was significantly lower than in the case group. In contrast to our results, of 940 term and preterm newborns, gestational age in the IVF group was significantly lower than in the non-IVF group (31 vs. 32, P<0.001) (12). IVH occurrence was independent of gestational age (GA) and is frequently happened within the first 24-48 h after birth (18). Regarding birth weight, no difference was observed between 2 groups. This finding was confirmed by another study (19).
Our main finding revealed that IVF as an independent risk factor could develop high-grade IVH. We could not find any associations between  and cystic periventricular leukomalacia and multiple gestations (22).
A limitation of our study was few numbers of the IVF cases in our hospitals and a long time requirement for data gathering. However, we tried to solve this problem with retrograde method (historical cohort study) and multi-centered data gathering in more than one hospital.
Moreover we did not consider some other risk factors like birth length, respiratory distress syndrome, mechanical ventilation, antenatal steroids administration and Apgar score that certainly could provide more informative data.
In conclusion, the incidence of IVH in IVF group was significantly higher than in non-IVF group.
IVF conception itself is a risk factor for incidence for IVH and its higher grades. Multi gestation was a risk factor for IVH incidence in natural pregnancies.

Acknowledgement
We acknowledge the parent for their participation in this study. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.